In past reporting periods, we procured a series of de-identified primary uterine carcinosarcoma tumors and paired non-tumor tissues through the Cooperative Human Tissue Network, which is supported by the National Cancer Institute. A subset of tumor-normal pairs (n=16 pairs) were exome sequenced at the NIH Intramural Sequencing Center. Short sequence reads for each exome were aligned to the human reference sequence and sequence variants in the normal and tumor exomes by called by our NHGRI collaborators Dr. Nancy Hansen and Dr. James Mullikin. The variant calls consisted of germline variants (present in both tumor and normal DNAs), somatic variants (present in tumor and matched normal DNAs) and false positive calls. In work that was jointly led by former Postdoctoral fellow Dr. Matthieu Le Gallo and Biologist Meghan Rudd, my laboratory rigorously analyzed the exome variants to identify those that were somatic and exclude germline variants and false positive calls. Next, we orthogonally validated somatic variants calls using Sanger sequencing. We subsequently prioritized a subset of validated somatically mutated genes, referred to as genes-of-interest, for further analysis in a mutation prevalence screen. The purpose of the prevalence screen was to rigorously define the frequency and spectrum of mutations among genes-of-interest in a larger cohort of primary uterine carcinosarcomas. Our investigations identified frequent and recurrent somatic mutations of FOXA2 in uterine carcinosarcomas. FOXA2 mutations have not previously been reported in uterine carinosarcomas, leading us to propose that FOXA2 is a novel putative driver gene for this malignancy. Because most uterine carcinosarcomas originate from endometrial carcinomas that undergo a metaplastic transition, we extended our analysis to sequence FOXA2 in 160 endometrial carcinomas (within project HG-200338-11). We identified frequent and recurrent FOXA2 mutations in serous, clear cell, and uterine endometrial cancers, implicating this gene as a driver gene in a subset of endometrial carcinomas. In the previous reporting period, we completed the experimental portion of this project and were preparing a manuscript describing our findings. In the current reporting period we completed the manuscript, and it has been accepted for publication in Cancer. A longer-term aim of this study is to determine the genomic etiology of uterine carcinosarcomas that arise in women who have a prior history of tamoxifen use. We hypothesize that the mutational landscape differs between carcinosarcomas arising in tamoxifen users versus non-users. In the incoming reporting period, we will initiate efforts to obtain clinical specimens for future studies designed to test this hypothesis.